US4489095A - Halogenobenzhydrylsulfinylacetohydroxamic acids - Google Patents
Halogenobenzhydrylsulfinylacetohydroxamic acids Download PDFInfo
- Publication number
- US4489095A US4489095A US06/498,592 US49859283A US4489095A US 4489095 A US4489095 A US 4489095A US 49859283 A US49859283 A US 49859283A US 4489095 A US4489095 A US 4489095A
- Authority
- US
- United States
- Prior art keywords
- crl
- dose
- acid
- hrs
- mouse
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- 239000002253 acid Substances 0.000 title abstract description 7
- 150000007513 acids Chemical class 0.000 title abstract description 3
- CGNMLOKEMNBUAI-UHFFFAOYSA-N adrafinil Chemical class C=1C=CC=CC=1C(S(=O)CC(=O)NO)C1=CC=CC=C1 CGNMLOKEMNBUAI-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- 230000001225 therapeutic effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 abstract description 5
- 229910052801 chlorine Inorganic materials 0.000 abstract description 5
- 229910052731 fluorine Inorganic materials 0.000 abstract description 5
- 239000000126 substance Substances 0.000 abstract description 5
- 239000003814 drug Substances 0.000 abstract description 2
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 2
- 229960002820 adrafinil Drugs 0.000 description 15
- 241000699666 Mus <mouse, genus> Species 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 12
- 230000004899 motility Effects 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 241000700159 Rattus Species 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000005843 halogen group Chemical group 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- VMWNQDUVQKEIOC-CYBMUJFWSA-N apomorphine Chemical compound C([C@H]1N(C)CC2)C3=CC=C(O)C(O)=C3C3=C1C2=CC=C3 VMWNQDUVQKEIOC-CYBMUJFWSA-N 0.000 description 6
- 229960004046 apomorphine Drugs 0.000 description 6
- 206010021143 Hypoxia Diseases 0.000 description 5
- RSDOPYMFZBJHRL-UHFFFAOYSA-N Oxotremorine Chemical compound O=C1CCCN1CC#CCN1CCCC1 RSDOPYMFZBJHRL-UHFFFAOYSA-N 0.000 description 5
- 206010039897 Sedation Diseases 0.000 description 5
- 210000003169 central nervous system Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000036280 sedation Effects 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- FTOAOBMCPZCFFF-UHFFFAOYSA-N 5,5-diethylbarbituric acid Chemical compound CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 230000002539 anti-aggressive effect Effects 0.000 description 4
- 230000000994 depressogenic effect Effects 0.000 description 4
- 230000002631 hypothermal effect Effects 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000002269 spontaneous effect Effects 0.000 description 4
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 3
- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 3
- 206010002660 Anoxia Diseases 0.000 description 3
- 241000976983 Anoxia Species 0.000 description 3
- 229920000084 Gum arabic Polymers 0.000 description 3
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 3
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 3
- 241000978776 Senegalia senegal Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 206010042008 Stereotypy Diseases 0.000 description 3
- 235000010489 acacia gum Nutrition 0.000 description 3
- 239000000205 acacia gum Substances 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229940025084 amphetamine Drugs 0.000 description 3
- 230000007953 anoxia Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000006399 behavior Effects 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- 230000005284 excitation Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 239000007928 intraperitoneal injection Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 3
- 229960003147 reserpine Drugs 0.000 description 3
- 230000029058 respiratory gaseous exchange Effects 0.000 description 3
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 206010052804 Drug tolerance Diseases 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 206010044565 Tremor Diseases 0.000 description 2
- 230000016571 aggressive behavior Effects 0.000 description 2
- 229960002319 barbital Drugs 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000001713 cholinergic effect Effects 0.000 description 2
- REEUVFCVXKWOFE-UHFFFAOYSA-K gallamine triethiodide Chemical compound [I-].[I-].[I-].CC[N+](CC)(CC)CCOC1=CC=CC(OCC[N+](CC)(CC)CC)=C1OCC[N+](CC)(CC)CC REEUVFCVXKWOFE-UHFFFAOYSA-K 0.000 description 2
- 230000026781 habituation Effects 0.000 description 2
- 230000001146 hypoxic effect Effects 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 238000005192 partition Methods 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000000932 sedative agent Substances 0.000 description 2
- 230000001624 sedative effect Effects 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007929 subcutaneous injection Substances 0.000 description 2
- 238000010254 subcutaneous injection Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- XIKDCTOOTIQHKL-UHFFFAOYSA-N 2,2-difluoro-3,3-diphenylpropanethioic s-acid Chemical compound C=1C=CC=CC=1C(C(F)(F)C(=S)O)C1=CC=CC=C1 XIKDCTOOTIQHKL-UHFFFAOYSA-N 0.000 description 1
- XRRYLQNMAPKIBP-UHFFFAOYSA-N 2-[(4,4-difluorocyclohexa-1,5-dien-1-yl)-phenylmethyl]sulfinyl-n-hydroxyacetamide Chemical group C=1C=CC=CC=1C(S(=O)CC(=O)NO)C1=CCC(F)(F)C=C1 XRRYLQNMAPKIBP-UHFFFAOYSA-N 0.000 description 1
- XAXZJLNBZGYMOZ-UHFFFAOYSA-N 2-[(4-chlorophenyl)-phenylmethyl]sulfinyl-n-hydroxyacetamide Chemical compound C=1C=C(Cl)C=CC=1C(S(=O)CC(=O)NO)C1=CC=CC=C1 XAXZJLNBZGYMOZ-UHFFFAOYSA-N 0.000 description 1
- OFQCQIGMURIECL-UHFFFAOYSA-N 2-[2-(diethylamino)ethyl]-2',6'-dimethylspiro[isoquinoline-4,4'-oxane]-1,3-dione;phosphoric acid Chemical compound OP(O)(O)=O.O=C1N(CCN(CC)CC)C(=O)C2=CC=CC=C2C21CC(C)OC(C)C2 OFQCQIGMURIECL-UHFFFAOYSA-N 0.000 description 1
- HMXJTUIGIGGLOL-UHFFFAOYSA-N 2-benzhydrylsulfinyl-n-hydroxybutanamide Chemical compound C=1C=CC=CC=1C(S(=O)C(C(=O)NO)CC)C1=CC=CC=C1 HMXJTUIGIGGLOL-UHFFFAOYSA-N 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- HZEUOBYKRLIRKD-UHFFFAOYSA-N 3,3-bis(4-fluorophenyl)-n-hydroxypropanethioamide Chemical compound C=1C=C(F)C=CC=1C(CC(=S)NO)C1=CC=C(F)C=C1 HZEUOBYKRLIRKD-UHFFFAOYSA-N 0.000 description 1
- HMRXLTXJGIAZEZ-UHFFFAOYSA-N 3,3-bis(4-fluorophenyl)propanethioic s-acid Chemical compound C=1C=C(F)C=CC=1C(CC(=S)O)C1=CC=C(F)C=C1 HMRXLTXJGIAZEZ-UHFFFAOYSA-N 0.000 description 1
- NZBNGFNLYLXPHK-UHFFFAOYSA-N 3-(4,4-difluorocyclohexa-1,5-dien-1-yl)-n-hydroxy-3-phenylpropanethioamide Chemical compound C=1C=CC=CC=1C(CC(=S)NO)C1=CCC(F)(F)C=C1 NZBNGFNLYLXPHK-UHFFFAOYSA-N 0.000 description 1
- WRYCEBDYTMDMNG-UHFFFAOYSA-N 3-(4-chlorophenyl)-3-phenylpropanethioic s-acid Chemical compound C=1C=C(Cl)C=CC=1C(CC(=S)O)C1=CC=CC=C1 WRYCEBDYTMDMNG-UHFFFAOYSA-N 0.000 description 1
- MRCLXXDOVINKML-UHFFFAOYSA-N 3-(4-chlorophenyl)-n-hydroxy-3-phenylpropanethioamide Chemical compound C=1C=C(Cl)C=CC=1C(CC(=S)NO)C1=CC=CC=C1 MRCLXXDOVINKML-UHFFFAOYSA-N 0.000 description 1
- SFHYNDMGZXWXBU-LIMNOBDPSA-N 6-amino-2-[[(e)-(3-formylphenyl)methylideneamino]carbamoylamino]-1,3-dioxobenzo[de]isoquinoline-5,8-disulfonic acid Chemical compound O=C1C(C2=3)=CC(S(O)(=O)=O)=CC=3C(N)=C(S(O)(=O)=O)C=C2C(=O)N1NC(=O)N\N=C\C1=CC=CC(C=O)=C1 SFHYNDMGZXWXBU-LIMNOBDPSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- 206010010904 Convulsion Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010015995 Eyelid ptosis Diseases 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000006550 Mydriasis Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 101150108015 STR6 gene Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- -1 benzhydryl radical Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000000985 convulsing effect Effects 0.000 description 1
- 230000036461 convulsion Effects 0.000 description 1
- VKGUUSVYPXTWMA-UHFFFAOYSA-N crl-40,941 Chemical compound C=1C=C(F)C=CC=1C(S(=O)CC(=O)NO)C1=CC=C(F)C=C1 VKGUUSVYPXTWMA-UHFFFAOYSA-N 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 230000003438 effect on compound Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000035873 hypermotility Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 231100001160 nonlethal Toxicity 0.000 description 1
- FOPSSNCVNYONQI-UHFFFAOYSA-N o-methyl 3-(4,4-difluorocyclohexa-1,5-dien-1-yl)-3-phenylpropanethioate Chemical compound C=1C=CC=CC=1C(CC(=S)OC)C1=CCC(F)(F)C=C1 FOPSSNCVNYONQI-UHFFFAOYSA-N 0.000 description 1
- NFTXHHKCXDALCZ-UHFFFAOYSA-N o-methyl 3-(4-chlorophenyl)-3-phenylpropanethioate Chemical compound C=1C=C(Cl)C=CC=1C(CC(=S)OC)C1=CC=CC=C1 NFTXHHKCXDALCZ-UHFFFAOYSA-N 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 1
- 201000003004 ptosis Diseases 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007958 sleep Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940036051 sojourn Drugs 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
Definitions
- the present invention relates to new compounds belonging to the family of benzhydrylsulfinylacetohydroxamic acids and having at least one halogen group such as F, Cl, Br or CF 3 on one of the phenyl groups of the benzhydryl radical.
- the invention also relates to a method for preparing these new compounds and to the use thereof in therapeutics, particularly as substances active on the central nervous system (CNS).
- CNS central nervous system
- U.S. Pat. No. 4,066,686 discloses a certain number of benzhydrylsulfinyl-hydroxamic acids of formula ##STR2## (wherein n is 1, 2 or 3).
- the compounds of formula (Io) are also known to be substances which act on the CNS.
- benzhydrylsulfinylacetohydroxamic acid cf. Example 1 of the above-mentioned patent; Code No.: CRL 40028
- benzhydrylsufinylpropionhydroxamic acid cf. Example 6 of said patent; Code No.: CRL 40206
- benzhydrylsulfinylbutyrohydroxamic acid cf. Example 9 of said patent; Code No.: CRL 40278) are sedative substances.
- halogeno compounds of formula I, infra are substances (i) useful as psychotonic agents, and (ii) endowed with anti-aggressive properties.
- the psychotonic compound of the 3686 patent i.e., benzhydrylsulfinylacetohydroxamic acid, does not exhibit any anti-aggressive properties.
- the new derivatives of benzhydrylsulfinylacetohydroxamic acid according to the invention are characterized in that they are selected from the group consisting of the halogeno-benzhydrylsulfinylacetohydroxamic acids of general formula ##STR3## wherein X 1 is F, Cl, Br or CF 3 ; and
- X 2 which may be identical to or different from X 1 , is H, F, Cl, Br or CF 3 .
- the preferred compounds according to the invention are those which have in their structural formula the groups X 1 and X 2 in para position.
- the most interesting compound from the therapeutical point of view is 4,4-difluoro-benzhydrylsulfinylacetohydroxamic acid.
- Table I shows some examples of compounds according to the invention (Example 1-Example 8) and prior known homologues of the above-mentioned U.S. patent (A1-A3).
- the halogeno derivatives according to the invention are psychotonic agents. Like CRL 40028 (compound A1), they increase the spontaneous motility in the mouse and improve motorial recovery in the mouse in which the motility had been reduced both by habituation to its enclosure and by hypoxic aggression. On the other hand, CRL 40260 (compound A2) and CRL 40278 (compound A3) reduce the spontaneous motility in the mouse and do not bring about any recovery of the motorial activity in the mouse in which the motility had been reduced.
- the principle difference between the halogeno derivatives according to the invention and the psychotonic compound (A1) resides in the fact that said novel halogeno derivatives have anti-aggressive properties, whilst the known compound (A1) does not exhibit such properties.
- the modus operandi is as follows: After having spent 3 weeks in each half of a cage separated by an opaque partition, groups of three male mice (four cages per compound and per dose) receive the compounds to be tested by the intraperitioneal route in suspension in an aqueous solution of gum arabic, the control animals (six cages) receiving only the aqueous solution of gum arabic. Half an hour later, the two groups of the same cage are brought together by removing the opaque partition and the number of fights which occur in 10 minutes is noted.
- a therapeutical composition which is characterized in that it contains, in association with a physiologically acceptable excipient, at least one compound of formula I as active ingredient.
- the active ingredient will, of course, be used at a pharmaceutically effective dose.
- halogeno derivatives according to the invention may be prepared according to a method known per se by application of conventional reaction mechanisms.
- the recommended method successively comprises
- the oily residue which essentially comprises methyl 4,4-difluorobenzhydrylthioacetate, is treated overnight at 20° C. with a solution obtained with 2.3 g (0.1 Atg) of sodium, 3.5 g (0.05 mol) of hydroxylamine hydrochloride and 160 ml of anhydrous methanol.
- CRL 40941 product of Example 1
- results of the tests carried out with CRL 40941 concerning its neuropsychopharmacological properties are summarized hereinbelow.
- CRL 40941 was administered by the intraperitoneal route, in suspension in an aqueous solution of gum arabic, in a volume of 20 ml/kg in the male mouse, and in a volume of 5 ml/kg in the male rat.
- the LD-0 (maximum non-lethal dose) of CRL 40941 by the IP route in the male mouse is higher than 512 mg/kg.
- mice receiving 1024 mg/kg IP of CRL 40941 present abdominal cramps, depressed respiration, and sedation 45 mins. after administration, then die 24 hours after administration.
- hypothermia (-1.9° C.) for 3 hrs.
- CRL 40941 leaves unchanged the hypothermia, the posture of verticalization and the stereotypies induced by apomorphine in the mouse.
- CRL 40941 is administered to batches of 6 rats half an hour before the sub-cutaneous injection of 0.5 mg/kg of apomorphine. It is observed that, particularly at the dose of 128 mg/kg, CRL 40941 prolongs the duration of the stereotypies produced by apomorphine in the rat, whilst CRL 40028, already known, at the dose of 256 mg/kg, does not modify the stereotyped behaviour induced by apomorphine in the rat.
- the amphetamine (2 mg/kg) is injected by the intraperitoneal route to batches of 6 rats half an hour after administration of CRL 40941. It is observed that, particularly at the dose of 128 mg/kg, CRL 40941 potentializes the amphetaminic stereotypies in duration, whilst CRL 40028 at the dose of 256 mg/kg does not modify the stereotype behaviour due to amphetamine.
- CRL 40941 Four hours after the intraperitoneal injection of 2.5 mg/kg of reserpine, batches of 6 mice receive CRL 40941. It is noted that, at a high dose (128 mg/kg), CRL 40941 very moderately reduces the intensity of the ptosis induced by reserpine but does not modify the hypothermia.
- CRL 40941 is administered to batches of 6 mice half an hour before the intraperitoneal injection of 0.5 mg/kg of oxotremorine.
- CRL 40941 opposes very partially the hypothermia-inducing action of oxotremorine, but this very limited antagonism does not increase with the dose.
- CRL 40941 does not substantially modify the tremors due to oxotremorine.
- CRL 40941 leaves virtually unchanged the signs of peripheral cholinergic stimulation produced by oxotremorine.
- the test is carried out on batches of 10 mice, half an hour after the administration of CRL 40941.
- CRL 40941 does not increase the number of passes which entail pain. It does not provoke any major motorial deficit and, unlike CRL 40028 mentioned above, it does not modify the convulsivant and lethal effects of the electric shock.
- mice (6 per batch, 12 controls) are placed in an activity-meter where their motility is recorded for 30 mins.
- CRL 40941 stimulates the spontaneous motorial activity of the mouse.
- mice After 18 hrs. sojourn in the activity-meters, the mice (6 per dose, 12 controls) receive CRL 40941. They are immediately returned to their respective enclosures and, half an hour later, their motility is recorded for 30 mins.
- CRL 40941 provokes a very clear resumption of the activity in the mouse habituated to its encosure. At a lower dose (4 and 16 mg/kg), this effect is less distinct.
- mice Half an hour after having received CRL 40941, the mice (10 per dose, 20 controls) are subjected to an acute hypobar anoxia [depression of 600 mm Hg (i.e. about 8 ⁇ 10 4 Pa) in 90 s, then expansion of 45 s], then they are placed in an activity meter where their mobility is recorded for 10 mins.
- an acute hypobar anoxia depression of 600 mm Hg (i.e. about 8 ⁇ 10 4 Pa) in 90 s, then expansion of 45 s
- CRL 40941 brings about an improvement in the motorial recovery in the mouse whose motility had been depressed further to a brief spell in an enclosure at reduced pressure.
- CRL 40941 shortens the time of appearance of convulsions and death consecutive to an asphyxic anoxia provoked by gallamine triiodoethylate which is a reference curariform.
- CRL 40941 clearly reduces the duration of sleep induced by the barbiturate.
- CRL 40941 has neuropsychopharmacological properties similar to those of CRL 40028 which is a known psychotonic agent. It differs from the latter by its anit-agressive properties and its action with respect to electric shock.
- CRL 40941 presents another advantage over CRL 40028 regarding assimilation by the oral route; in fact, CRL 40941, as psychotonic agent, is clearly more effective by the oral route, in the rat and in man, than CRL 40028.
- CRL 40941 acts at doses which are half those of CRL 40028. Excellent results were obtained in man when it was administered per os, at the rate of 2 to 3 capsules or tablets (each containing 50 mg of active ingredient) per day, particularly for 2 to 8 weeks in the treatment of hypersommia and psychastenia.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Public Health (AREA)
- Psychiatry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
TABLE I ______________________________________ ##STR4## Effect on Compound Code No. X.sub.1 X.sub.2 n the CNS ______________________________________ Example 1 CRL 40941 4-F 4-F 1 (b) Example 2 CRL 40933A 4-Cl H 1 (b) Example 3 CRL 41018A 4-F H 1 (b) Example 4 CRL 40933B 4-Cl 4-Cl 1 (b) Example 5 -- 4-Br 4-Br 1 (b) Example 6 -- 4-CF.sub.3 H 1 (b) Example 7 -- 4-CF.sub.3 4-CF.sub.3 1 (b) Example 8 -- 4-Br H 1 (b) A1 (a) CRL 40028 H H 1 (b) A2 (a) CRL 40260 H H 2 (c) A3 (a) CRL 40278 H H 3 (c) ______________________________________ Notes: (a) described in U.S. Pat. No. 4 066 (b) psychotonic (c) sedative
TABLE II ______________________________________ Dose Variation of inter- Compound Code No. mg/kg group aggressiveness ______________________________________ Example 1 CRL 40941 256 (a) -20% Example 1 CRL 40941 128 -61% Example 1 CRL 40941 64 -58% Example 2 CRL 40933A 256 (a) -22% Example 2 CRL 40933A 128 -57% Example 2 CRL 40933A 64 -51% A1 CRL 40028 256 (a) +36% A1 CRL 40028 128 -3% A1 CRL 40028 64 +2% ______________________________________ Note (a) dose provoking excitation in the mouse
Claims (2)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR8209805 | 1982-06-04 | ||
FR8209805A FR2528041A1 (en) | 1982-06-04 | 1982-06-04 | HALOGENOBENZHYDRYLSULFINYLACETOHYDROXAMIC ACIDS, PREPARATION METHOD AND THERAPEUTIC USE |
Publications (1)
Publication Number | Publication Date |
---|---|
US4489095A true US4489095A (en) | 1984-12-18 |
Family
ID=9274666
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US06/498,592 Expired - Lifetime US4489095A (en) | 1982-06-04 | 1983-05-26 | Halogenobenzhydrylsulfinylacetohydroxamic acids |
Country Status (10)
Country | Link |
---|---|
US (1) | US4489095A (en) |
EP (1) | EP0097547B1 (en) |
JP (1) | JPS591458A (en) |
AT (1) | ATE15186T1 (en) |
CA (1) | CA1192222A (en) |
DE (1) | DE3360669D1 (en) |
DK (1) | DK157810C (en) |
ES (1) | ES8403863A1 (en) |
FR (1) | FR2528041A1 (en) |
IE (1) | IE54977B1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5571825A (en) * | 1995-03-31 | 1996-11-05 | Warner-Lambert Company | Method of selectively inhibiting prostaglandin G/H synthase-2 |
US6492396B2 (en) | 2000-05-16 | 2002-12-10 | Cephalon, Inc. | Substituted thioacetamides |
US6670358B2 (en) | 2000-05-16 | 2003-12-30 | Cephalon, Inc. | Substituted thioacetamides |
US20060160903A1 (en) * | 2003-02-24 | 2006-07-20 | Sidney Liang | Process for preparing benzhydrylthioacetamide |
WO2012078800A2 (en) | 2010-12-08 | 2012-06-14 | Codexis, Inc. | Biocatalysts and methods for the synthesis of armodafinil |
CN104059004A (en) * | 2014-06-25 | 2014-09-24 | 江苏斯威森生物医药工程研究中心有限公司 | Method for preparing 2-[(4,4'-dihalo-diphenyl methyl) sulfydryl] acetate |
US9637447B2 (en) | 2011-01-20 | 2017-05-02 | Nls Pharma Ag | Lauflumide and the enantiomers thereof, method for preparing same and therapeutic uses thereof |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2606015B1 (en) * | 1986-08-13 | 1989-05-19 | Lafon Labor | BENZHYDRYLTHIOMETHANE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THERAPEUTIC APPLICATIONS |
FR2602768B1 (en) * | 1986-08-13 | 1989-02-03 | Lafon Labor | 2- (4,4'-DIFLUORO BENZHYDRYL THIO) ACETIC ACID DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THERAPEUTIC APPLICATIONS |
JP2521595B2 (en) * | 1991-07-04 | 1996-08-07 | 江崎グリコ株式会社 | Manufacturing method of polished rice cake |
US6172057B1 (en) | 1997-02-27 | 2001-01-09 | American Cyanamid Company | N-Hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors |
SK115899A3 (en) * | 1997-02-27 | 2000-05-16 | American Cyanamid Co | N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors |
EP1437345A1 (en) * | 2003-01-13 | 2004-07-14 | Organisation de Synthese Mondiale Orsymonde | Novel method for preparing methyl 2-diphenylmethylsulfinylacetate |
Citations (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2483671A (en) * | 1947-06-02 | 1949-10-04 | Parke Davis & Co | Aminoalkyl benzhydryl thioethers and their preparation |
US2618637A (en) * | 1950-03-18 | 1952-11-18 | Sterling Drug Inc | Tertiary - aminoalkyl diarylmethyl sulfones and their preparation |
US3157650A (en) * | 1962-09-04 | 1964-11-17 | Cilag Chemie | Amides of 2-aryl-ethanoic acids |
US3549691A (en) * | 1966-06-23 | 1970-12-22 | Ici Ltd | Aralkyloxy alkanoic acids |
US3789072A (en) * | 1970-04-22 | 1974-01-29 | Squibb & Sons Inc | Carboxamides |
US3993683A (en) * | 1974-05-20 | 1976-11-23 | Boehringer Ingelheim Gmbh | Biphenylyl derivatives |
US4013776A (en) * | 1974-09-30 | 1977-03-22 | Societe Anonyme Dite: Laboratoire L. Lafon | Phenylsulphinyl-amidine derivatives |
FR2326181A1 (en) * | 1975-10-02 | 1977-04-29 | Lafon Labor | NEW BENZHYDRYLSULFINYL DERIVATIVES |
US4062973A (en) * | 1975-10-16 | 1977-12-13 | Boehringer Ingelheim Gmbh | Sulfur-containing derivatives of cyclohexylphenyl-ethane |
US4122186A (en) * | 1976-03-23 | 1978-10-24 | Laboratoire L. Lafon | Acetohydroxamic acids |
FR2385693A1 (en) * | 1977-03-31 | 1978-10-27 | Lafon Labor | ACETAMIDE DERIVATIVES USEFUL PARTICULARLY IN THERAPEUTICS |
US4134996A (en) * | 1976-08-16 | 1979-01-16 | The Dow Chemical Company | Method for inhibiting adp-induced platelet aggregation using phenylthioalkylamines |
US4156011A (en) * | 1974-09-30 | 1979-05-22 | Societe Anonyme Dite: Laboratoire L. Lafon | Sulphur- and oxygen-containing diaryl compounds |
US4183927A (en) * | 1976-08-16 | 1980-01-15 | The Dow Chemical Company | Substituted phenylthioalkylamines and compositions thereof |
US4199597A (en) * | 1979-05-04 | 1980-04-22 | Schering Corporation | Omega-(4-polyfluoro-2-hydroxy-2-propyl)-2,3,6-substituted-phenoxy and phenylthio)alkanoic acids and compounds related thereto |
EP0061406A1 (en) * | 1981-03-25 | 1982-09-29 | LABORATOIRE L. LAFON Société anonyme dite: | Benzamido-alkyl-hydroxamic-acid derivatives, preparation thereof and therapeutical composition |
-
1982
- 1982-06-04 FR FR8209805A patent/FR2528041A1/en active Granted
-
1983
- 1983-05-20 IE IE1193/83A patent/IE54977B1/en not_active IP Right Cessation
- 1983-05-26 EP EP83401049A patent/EP0097547B1/en not_active Expired
- 1983-05-26 AT AT83401049T patent/ATE15186T1/en not_active IP Right Cessation
- 1983-05-26 US US06/498,592 patent/US4489095A/en not_active Expired - Lifetime
- 1983-05-26 DE DE8383401049T patent/DE3360669D1/en not_active Expired
- 1983-05-27 CA CA000429082A patent/CA1192222A/en not_active Expired
- 1983-06-03 DK DK253383A patent/DK157810C/en not_active IP Right Cessation
- 1983-06-03 ES ES522984A patent/ES8403863A1/en not_active Expired
- 1983-06-04 JP JP58098797A patent/JPS591458A/en active Granted
Patent Citations (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2483671A (en) * | 1947-06-02 | 1949-10-04 | Parke Davis & Co | Aminoalkyl benzhydryl thioethers and their preparation |
US2618637A (en) * | 1950-03-18 | 1952-11-18 | Sterling Drug Inc | Tertiary - aminoalkyl diarylmethyl sulfones and their preparation |
US3157650A (en) * | 1962-09-04 | 1964-11-17 | Cilag Chemie | Amides of 2-aryl-ethanoic acids |
US3549691A (en) * | 1966-06-23 | 1970-12-22 | Ici Ltd | Aralkyloxy alkanoic acids |
US3789072A (en) * | 1970-04-22 | 1974-01-29 | Squibb & Sons Inc | Carboxamides |
US3993683A (en) * | 1974-05-20 | 1976-11-23 | Boehringer Ingelheim Gmbh | Biphenylyl derivatives |
US4156011A (en) * | 1974-09-30 | 1979-05-22 | Societe Anonyme Dite: Laboratoire L. Lafon | Sulphur- and oxygen-containing diaryl compounds |
US4013776A (en) * | 1974-09-30 | 1977-03-22 | Societe Anonyme Dite: Laboratoire L. Lafon | Phenylsulphinyl-amidine derivatives |
FR2326181A1 (en) * | 1975-10-02 | 1977-04-29 | Lafon Labor | NEW BENZHYDRYLSULFINYL DERIVATIVES |
US4066686A (en) * | 1975-10-02 | 1978-01-03 | Laboratoire L. Lafon | New benzhydrysulphinyl derivatives |
US4062973A (en) * | 1975-10-16 | 1977-12-13 | Boehringer Ingelheim Gmbh | Sulfur-containing derivatives of cyclohexylphenyl-ethane |
US4122186A (en) * | 1976-03-23 | 1978-10-24 | Laboratoire L. Lafon | Acetohydroxamic acids |
US4134996A (en) * | 1976-08-16 | 1979-01-16 | The Dow Chemical Company | Method for inhibiting adp-induced platelet aggregation using phenylthioalkylamines |
US4183927A (en) * | 1976-08-16 | 1980-01-15 | The Dow Chemical Company | Substituted phenylthioalkylamines and compositions thereof |
FR2385693A1 (en) * | 1977-03-31 | 1978-10-27 | Lafon Labor | ACETAMIDE DERIVATIVES USEFUL PARTICULARLY IN THERAPEUTICS |
US4177290A (en) * | 1977-03-31 | 1979-12-04 | Laboratoire L. Lafon | Acetamide derivatives |
US4199597A (en) * | 1979-05-04 | 1980-04-22 | Schering Corporation | Omega-(4-polyfluoro-2-hydroxy-2-propyl)-2,3,6-substituted-phenoxy and phenylthio)alkanoic acids and compounds related thereto |
EP0061406A1 (en) * | 1981-03-25 | 1982-09-29 | LABORATOIRE L. LAFON Société anonyme dite: | Benzamido-alkyl-hydroxamic-acid derivatives, preparation thereof and therapeutical composition |
Non-Patent Citations (3)
Title |
---|
Buraczewski, et al., Bull. Acad. Polon. Sci. Ser. Sci. Chim. vol. XII No. 11, 1964. * |
J. Org. Chem., vol. 32, Oct. 1967, pp. 3191 3194. * |
J. Org. Chem., vol. 32, Oct. 1967, pp. 3191-3194. |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5571825A (en) * | 1995-03-31 | 1996-11-05 | Warner-Lambert Company | Method of selectively inhibiting prostaglandin G/H synthase-2 |
US7268132B2 (en) | 2000-05-16 | 2007-09-11 | Cephalon, Inc. | Substituted thioacetamides |
US6670358B2 (en) | 2000-05-16 | 2003-12-30 | Cephalon, Inc. | Substituted thioacetamides |
US20040116445A1 (en) * | 2000-05-16 | 2004-06-17 | Bacon Edward R. | Substituted thioacetamides |
US6919367B2 (en) | 2000-05-16 | 2005-07-19 | Cephalon, Inc. | Substituted thioacetamides |
US20050192313A1 (en) * | 2000-05-16 | 2005-09-01 | Cephalon, Inc. | Substituted thioacetamides |
USRE39575E1 (en) * | 2000-05-16 | 2007-04-17 | Cephalon, Inc. | Substituted thioacetamides |
US6492396B2 (en) | 2000-05-16 | 2002-12-10 | Cephalon, Inc. | Substituted thioacetamides |
US20060160903A1 (en) * | 2003-02-24 | 2006-07-20 | Sidney Liang | Process for preparing benzhydrylthioacetamide |
US7244865B2 (en) | 2003-02-24 | 2007-07-17 | Mallinckrodt Inc. | Process for preparing benzhydrylthioacetamide |
WO2012078800A2 (en) | 2010-12-08 | 2012-06-14 | Codexis, Inc. | Biocatalysts and methods for the synthesis of armodafinil |
US9637447B2 (en) | 2011-01-20 | 2017-05-02 | Nls Pharma Ag | Lauflumide and the enantiomers thereof, method for preparing same and therapeutic uses thereof |
CN104059004A (en) * | 2014-06-25 | 2014-09-24 | 江苏斯威森生物医药工程研究中心有限公司 | Method for preparing 2-[(4,4'-dihalo-diphenyl methyl) sulfydryl] acetate |
Also Published As
Publication number | Publication date |
---|---|
DE3360669D1 (en) | 1985-10-03 |
DK253383A (en) | 1983-12-05 |
JPS6136829B2 (en) | 1986-08-20 |
DK157810B (en) | 1990-02-19 |
EP0097547B1 (en) | 1985-08-28 |
JPS591458A (en) | 1984-01-06 |
EP0097547A1 (en) | 1984-01-04 |
IE831193L (en) | 1983-12-04 |
DK157810C (en) | 1990-07-09 |
IE54977B1 (en) | 1990-04-11 |
FR2528041B1 (en) | 1985-02-08 |
ATE15186T1 (en) | 1985-09-15 |
ES522984A0 (en) | 1984-03-01 |
CA1192222A (en) | 1985-08-20 |
FR2528041A1 (en) | 1983-12-09 |
DK253383D0 (en) | 1983-06-03 |
ES8403863A1 (en) | 1984-03-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1199916A (en) | Benzhydrylsulfinylacetamide derivatives | |
US4489095A (en) | Halogenobenzhydrylsulfinylacetohydroxamic acids | |
DE2642511C2 (en) | Benzhydrylsulfinyl compounds, processes for their preparation and pharmaceuticals containing these compounds | |
US4148923A (en) | 1-(3'-Trifluoromethylthiophenyl)-2-ethylaminopropane pharmaceutical composition and method for treating obesity | |
FR2460919A1 (en) | AMINO-ETHERS OXIDES, PROCESS FOR PREPARING THEM AND THEIR THERAPEUTIC APPLICATION | |
US4584321A (en) | 3-(3-Hydroxybutoxy)-1-butanol in pharmaceutical compositions | |
EP0025192B1 (en) | Substituted oxirane carboxylic acids, process for their preparation, their use and medicines containing them | |
IE48368B1 (en) | Imidazole derivatives | |
EP0047536A2 (en) | Substituted propylamines | |
EP0074014B1 (en) | 2-(2'-hydroxy-3'-(1,1,-dimethyl propylamino)-propoxy)-beta propiophenone, its addition salts, process for its preparation and medicaments | |
US3205136A (en) | Antidepressant phenyloxyalkylamines | |
EP0046961B1 (en) | Epoxy-cycloalkylalkanecarboxylic acids, process for their preparation, their use and medicaments containing them | |
EP0082461B1 (en) | Substituted phenoxyalkanol amines and phenoxyalkanol-cycloalkyl amines, process for their preparation, pharmaceutical compositions containing them and intermediates | |
US4407822A (en) | Benzamido-alkyl-hydroxamic acid derivatives | |
US4011340A (en) | Hypolipidemic bis(pivaloylbenzyl) ureas | |
US4196206A (en) | Pyridyl-piperazine derivative with anti-arrythmic effect | |
EP0338937A2 (en) | 1-[3-(4-Hydroxy-phenyl)-1-hydoxy-1-propyl]-2-(amino-alkyleneoxy)-benzene derivatives, process for their preparation and their therapeutical use | |
JPS6322070A (en) | Novel derivative of n-(3-(2,4,6-trimethoxybenzoyl)propyl)piperidine,manufacture and remedy therefrom | |
DD150060A5 (en) | PROCESS FOR THE PREPARATION OF NEW PHENTHIAZINE DERIVATIVES | |
US3551491A (en) | 4 - halothymyl - (n - ethyl - n - beta - chloroethyl - 1- and-2 - amino propyl(2) and (1)) ether and salts thereof | |
US4545996A (en) | N-(4-Acetylaminophenacyl)amine derivatives useful as pharmaceuticals | |
DE3216986A1 (en) | 2-METHOXYPHENYL ESTER OF N-SUBSTITUTED AMINO ACIDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL THESE COMPOUNDS | |
US4084003A (en) | Pivaloyl benzyl amines and method of use thereof | |
DE1929839C (en) | 4-tertiary-aminomethyl-7-hydroxy = coumarins and choleretics containing them | |
US4690950A (en) | 1-[N-(α-amino-α-methylacetyl)aminophenyl]-2-aminopropanone derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: SOCIETE ANONYME STYLED: LABORATOIRE L. LAFON, 1, R Free format text: ASSIGNMENT OF ASSIGNORS INTEREST.;ASSIGNOR:LAFON, LOUIS;REEL/FRAME:004137/0300 Effective date: 19830513 |
|
STCF | Information on status: patent grant |
Free format text: PATENTED CASE |
|
CC | Certificate of correction | ||
FPAY | Fee payment |
Year of fee payment: 4 |
|
FEPP | Fee payment procedure |
Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
FPAY | Fee payment |
Year of fee payment: 8 |
|
FEPP | Fee payment procedure |
Free format text: PAYER NUMBER DE-ASSIGNED (ORIGINAL EVENT CODE: RMPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY Free format text: PAYOR NUMBER ASSIGNED (ORIGINAL EVENT CODE: ASPN); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
FEPP | Fee payment procedure |
Free format text: PAT HLDR NO LONGER CLAIMS SMALL ENT STAT AS SMALL BUSINESS (ORIGINAL EVENT CODE: LSM2); ENTITY STATUS OF PATENT OWNER: LARGE ENTITY |
|
FPAY | Fee payment |
Year of fee payment: 12 |